Despite the progress that has been made in the treatment of lymphoid malignancies, such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), the majority of patients with each of these diseases eventually develop resistance and ultimately die from their leukemia. In ALL and CLL, mechanisms of resistance have been shown to involve alternation in Bcl-2 family member expression that prevents apoptosis and aberrant signaling through the PKC, PI3 kinase/AKT, and ERK pathways in part mediated through stromal cell interactions. New therapies that act through novel mechanisms of action that either act independent of Bcl-2 family member expression and/or antagonize aberrant signal transduction pathways are therefore needed for both CLL and ALL. Normal lymphocytes utilize serine/threonine phosphatases such as PP1, PP2A, and PP2B to both inactivate signal transduction pathways and antagonize the action of Bcl-2 family members including Bcl-2 and Bad. In B-cell lymphoproliferative disorders, these same phosphatases are often silenced, a process that may contribute further to the drug resistance observed in these diseases. Therapeutic agents that activate serinine/threonine phosphatases such as PP2A have not been tested in the clinic for CLL and ALL.
FTY720 (2-Amino-2-[2-(4-octylphenyl) ethyl]propane 1,3-diol hydrochloride) is a synthetic compound produced by modification of a natural immunosuppressant, ISP-1. FTY720 was noted to interfere in T-cell trafficking and in pre-clinical studies was demonstrated to prolong survival of transplanted allograft organs without noticeable toxicity to the host. Early phase I/II clinical studies of FTY720 to treat and prevent organ rejection demonstrated promise. As a consequence, FTY720 is currently in Phase III clinical trials as immunosuppressant for renal transplant rejection. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues. FTY720 is phosphorylated by sphingosine kinase and the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors which modulate chemotactic responses and lymphocyte trafficking. FTY720 has been shown to bind to the sphingosine-1-phosphate (S1P) receptor, resulting in decreased number of circulating mature lymphocytes by acceleration of lymphocyte homing. Previous studies have also suggested that FTY720 might also promote activation of the serine/threonine phosphatase PP2A.